Oxime ether anti-depressants

ABSTRACT

Compositions containing and methods employing novel alkylthioalkyl oxime ethers and the corresponding nitrones, useful as CNS agents, particularly anti-depressants. Methods for preparing these compounds and compositions are also disclosed. O(Methylthiomethyl)-benzophenone oxime is illustrated as representative of the class.

United States Patent Moffatt Sept. 11, 1973 [5 OXIME ETHER ANTl-DEPRESSANTS 3,526,671 9/1970 Judd 260/566 AB [75] lnventor: John G. Moffatt, Los Altos, Calif. [73] Assignee: Syntex Corporation, Panama, Primary Emmi'fer Leon Ziwer Assistant ExammerGerald A. Schwartz Panama [22] F] d A 14 1970 A1torneyWalter H. Dreger and Evelyn K. Merker 1 e ug.

[21] Appl. No.: 63,920

[57] ABSTRACT [52] US. Cl. 260/566 AE, 260/327 R, 260/327 TH,

. pos1t1ons contalnmg and methods employing novel 1 260/3292 260/3323 260/999 260/566 R alkylthioalkyl oxime ethers and the corresponding nitrones useful as g particularly anti 1 0 260/566 327 depressants. Methods for preparing these compounds 260/327 3323 566 R and compositions are also disclosed. O-(Methylthiomethyl)-benzophenone oxime is illustrated as representa- Reterences CIted tive of the class UNITED STATES PATENTS 7/l969 Van der Stelt 260/566 AE X 6 Claims, No Drawings 1 OXIME ETHER ANTl-DEPRESSANTS The present invention is directed to oxime ether compounds, compositions containing, and methods utilizing these compounds as CNS agents, particularly as having anti-depressant activity.

The first aspect of the present invention relates to a group of novel oxime ether compounds selected from those represented by the following formulas:

and the corresponding nitrones of the compounds of the above formulas; wherein,

each R is the same and in the same respective position of the two corresponding phenyl rings and selected from a group of substituents or one R is hydrogen and the other R is selected from a group of substituents, said group of substituents being hydrogen, alkyl of one to four carbon atoms, halo, nitro, dimethylamino, diethylamino, alkoxy of one to four carbon atoms, or alkylthio of one to four carbon atoms;

R is hydrogen, methyl, or ethyl;

R is alkyl of one to six carbon atoms, halomethyl,

phenyl, monosubstituted phenyl wherein the substituent is halo, nitro, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or halomethyl; or

R and R taken together is tetramethylene;

R is methylene or thio; and

Z is a carbon-carbon single bond or a carbon-carbon double bond;

provided that, in a compound of Formula (A) and its nitrone, when R is hydrogen and R is methyl, then at least one R is other than hydrogen.

The corresponding nitrones of the above compounds,

included within the scope of this invention, can be further described by the following formula:

ethylene, propylene, or

wherein X is the remainder of the nuclei depicted by the above formulas and each of R and R is as defined above.

The present invention, in a second aspect, is directed to a method of using the compounds of the present invention, or pharmaceutical compositions thereof as described hereinafter, to elicit an anti-depressant effect when administered to an animal in an anti-depressant effective amount. This aspect of the present invention thus relates to a method comprising administering to an animal an anti-depressant effective amount of a compound selected from those represented by Formulas (A), (B), (C), (D), (E), and (F) wherein each R is the same and in the same respective position of the two corresponding phenyl rings and selected from a group of substituents or one R is hydrogen and the other R is selected from a group of substituents, said group of substituents being hydrogen, alkyl of one to four carbon atoms, halo, nitro, dimethylamino, diethylamino, alkoxy of one to four carbon atoms, or alkylthio of one to four carbon atoms;

R is hydrogen, methyl, or ethyl;

R is alkyl of one to six carbon atoms, halomethyl,

phenyl, monosubstituted phenyl wherein the substituent is halo, nitro, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or halomethyl; or

R and R taken together is ethylene, propylene, or

tetramethylene;

R is methylene or thio; and

Z is a carbon-carbon single bond or a carbon-carbon double bond.

In the practice of this use, the compounds of the present invention, or compositions thereof, can be administered to an animal via any of the usual and accepted methods known in the art, whether parenterally or orally, either singly or in combination with other compounds of this invention or other pharmaceutical agents such as antibiotics, hormonal agents, etc. The administration can be conducted in single unit dosage form for continuous therapy or in single dose therapy. In view of the foregoing as well as in consideration of the degree or severity of the condition being treated, age of patient, and so forth, all of which factors being determinable by one skilled in the art; the dosage can vary over a wide range. Generally, an anti-depressant effective amount ranges from about I to about 50 and preferably from about 2 to about 10 mg/kg. of body weight per day.

The compounds of the present invention demonstrate antidepressant activity as measured by a test indicative of such as substantially described by B.M. Askew, Life Sci. 2, 725 (1963) and V.G. Vernier et al., ls! Hahnemann Sym. on Psychosomatic Medicine, Lea and Befiger, 1962, pp. 683 et seq.. This test involves the reversal of reserpine induced hypothermia back to normal mean resting temperature.

The present invention, in a third aspect, is directed to pharmaceutical compositions incorporating an antidepressant effective amount of a compound defined and depicted above. Such compositions will contain the active compound together with a solid or liquid pharmaceutically acceptable non-toxic carrier. Such pharmaceutical carriers can be solids or sterile liquids such as water and oils including those of petroleum, animal vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose and glycols are preferred liquid carriers particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. These compositions take the forms of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like. Suitable pharmaceutical carriers are described in Remingtons Pharmaceutical Sciences by E. W..

Martin. Such compositions will contain an antidepressant effective amount of the active compound together with a suitable amount of carrier so as to prepare the preferred dosage form for proper administration to the host. Typical compositions are prepared by filling standard two-piece gelatin capsules with active compound, lactose, and silica or with a suspension of active compound in mineral oil or by tableting active compound, gelatin, magnesium stearate, and lactose by conventional procedures. By coating the latter, slow release tablets can be prepared.

The compounds of the present invention are prepared by reacting together an oxime corresponding to the compounds depicted above of the partial formula:

wherein X is as defined above, and a halo, preferably chloro, reagent of the following formula:

wherein Y is halo and each of R and R is as defined above and a suitable base, such as an alkali metal hydride, preferably sodium hydride.

The reaction is preferably conducted in an inert liquid organic reaction media including those usually employed in organic chemical reactions such as benzene, diethyl ether, dioxane, tetrahydrofuran, and the like or suitable mixtures of one or more of such media. The reaction is further conducted at temperatures ranging from about l to about 100C. and for a period of time sufficient to complete the reaction ranging from about 0.5 to about three hours.

The reaction consumes the reactants on the basis of one mole of oxime compound per mole each of halo compound and suitable base. However, the amounts of the reactants to be employed are not critical, some of the desired oxime ether products being obtained when employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about 1.1 to about 1.5 moles of the halo compound and from about 1.1 to about 1.5 moles of base per mole of starting oxime compound. The inert liquid reaction media, if employed, is used in solvent amounts. I

In the practice of this step, the oxime and the base are first reacted so as to produce the metal salt of the oxime which is subsequently reacted with the halo compound within the given temperature range for a pe riod of time sufficient to produce product. Following the reaction, the product can be separated and isolated by use of conventional techniques such as extraction, distillation, sublimation, and chromatography. By use of more polar solvents in the chromatographic separation of products, such as ethyl acetate and concentration gradients of ethyl acetate in chloroform, methanol in benzene, etc.; the corresponding nitrone product, which is also prepared in the reaction, can be separated and isolated from the corresponding oxime ether prod- LICK.

The starting oxime compounds are known and they can be prepared by reaction of the ketone precursor with hydroxylamine hydrochloride in a base such as pyridine. The halo reagent starting compounds are known and they can be prepared, for example, by the a-halogenation of sulfides by known techniques such as those described in Journal of Organic Chemistry 34, 31 (1969), Zhur. Obsh. Khim. 27, 780 (i957), British Patent 772,213, and Journal of American Chemical Society 74, 3594. Alternatively, they can be prepared by the condensation of aldehydes or ketones with mercaptans in the presence of hydrogen chloride as in Ber., 69, l6l0 (1936), Ann. 563, 54 (1969) and J. Org. Chem. 34, 31(1969).

The term halo" refers to bromo, chloro, fiuoro, and iodo; the term halomethyl to mono-, di-, or trihalomethyl (halo as above defined), preferably trifluoromethyl. Alkyl is branched or straight chain; the various isomers.

The following examples illustrate the method by which the present invention can be practiced.

EXAMPLE 1 A solution of benzophenone (0.1 mole) and hydroxylamine hydrochloride (0.2 mole) in ISO ml. of pyridine is heated to l00C. and maintained at this temperature for from 30 to 60 minutes. After this time, the mixture is cooled to room temperature and then poured into one liter of ice water. The mixture is filtered and the filtered material washed with water and crystallized from ethanol to prepare the benzophenone oxime product.

In a. similar manner, the foregoing procedure can be used to prepare the other oxime starting compounds of the present invention, for example, the following:

4,4'-dimethylbenzophenone oxime,

2,2-dimethylbenzophenone oxime, 2,2-dichlorobenzophenone oxime, 4-nitrobenzophenone oxime, 4,4'-dichlorobenzophenone oxime, 3-dimethylaminobenzophenone oxime, 4,4'-dimethoxybenzophenone oxime, 4,4'-di(ethylthio)-benzophenone oxime, 2,2-di(dimethylamino)-benzophenone oxime, 4,4'-di(butylthio)-benzophenone oxime, 3-t-butylbenzophenone oxime, 2-fluorobenzophenone oxime, 4,4'-difluorobenzophenone oxime, 3,3-dimethoxybenzophenone oxime,

4,4'-dimethoxybenzophenone oxime, 5,5-dimethylbenzophenone oxime, a,a-dinaphthylketone oxime,

B,B-dinaphthylketne oxime, -oximinodibenzo[a,d]cycloheptene, 5-oximino-l0,1 l-dihydrodibenzo[a,d]cycloheptene, 9-oximinofiuorene,

l0-oximinoxanthene, and

IO-oximin othioxanthene.

EXAMPLE 2 To a solution of 0.1 mole of tetrahydrothiophene in 10 ml. of carbon tetrachloride is added0.l mole of N- chloro-succinimide with stirring. The resultant mixture is kept at about 4C. for six to seven hours after which time it is evaporated to remove the solvent and distilled in vacuo to provide 2-chlorotetrahydrothiophene.

The foregoing procedure is used to prepare the other chloro reagents of the present invention such as 2- chlorothietane and 2-chlorotetrahydrothiopyran, or the acyclic chain compounds can be prepared by the condensation of aldehydes or ketones with mercaptans and hydrogen chloride according to the method of Bohme as described in Her. 69, 1610 (1936) and Ann. 563, 54 ([949). By substitution of N- bromosuccinimide in the above procedure, the corresponding bromo reagents are prepared.

A dispersion of sodium hydride 14 mmol) in mineral oil is washed by centrifugation with hexane several times and then added to a solution of 5-oximino-l0,l ldihydrodibenzo-[a,d]cyclopentene (2.25 grams, l0 mmole) in anhydrous benzene (40 ml.). The mixture is stirred at 0C. for 30 minutes under nitrogen and then chloromethyl methylsulfide (1.3 grams, l3 mmoles) is added in a portionwise fashion while continuing the stirring. The temperature is then raised to and maintained at 80C. for one hour after which time the mix- EXAMPLE 4 A dispersion of sodium hydride (5 mmol) in mineral oil is washed by centrifugation with hexane several times and then added to a solution of benzophenone oxime (l mmoles) in anhydrous benzene (40 ml.). The mixture is stirred at 0C. for 30 minutes under nitrogen and then chloromethyl methylsulfide (5 mmoles) is added in a portionwise fashion while continuing the stirring. The temperature is maintained at C. for one hour after which time the mixture is cooled and filtered. The filtrate is washed with aqueous bicarbonate and then with water and dried over magnesium sulfate. The dried mixture is evaporated and the resultant residue dissolved in benzene: hexane (1:1) and applied to a column containing 250 grams of silicic acid. Elution with one liter of benzenezhexane followed by continued elution with benzene gives 0-(methyl-thiomethyl)- benzophenone oxime which can be crystallized from ethanol. Also prepared is the corresponding a,a-diphenyl N-(methylthiomethyl)-nitrone by continued elution with increasing amounts of methanol in benzene.

EXAMPLE 5 A dispersion of sodium hydride 10 moles) in mineral oil is washed by centrifugation with hexane several times and then added to a solution of benzophenone oxime (5 mmoles) in anhydrous benzene (40 ml.). The mixture is stirred for 30 minutes under nitrogen and then l-chloroethyl methyl-sulfide (1.3 grams, l3 mmoles) is added in a portionwise fashion while continuing the stirring. The temperature is maintained at 80C. for one hour after which time the mixture is cooled and filtered. The filtrate is washed with aqueous bicarbonate and then with water and dried over magnesium sulfate. The dried mixture is evaporated and the resultant residue dissolved in benzenezhexane (1:1) and applied to a column containing 250 grams of silicic acid. Elution with one liter of benzenezhexane followed by continued elution with benzene gives 0-( l-methylthioethyl)- benzophenone oxime which can be crystallized from ethanol. By continued elution with ethyl acetate:- chloroforrn a,a-diphenyl N-( l-methylthioethyl) nitrone is prepared.

In accordance with the foregoing general procedure, the starting materials listed under Column A below are reacted with the reagents listed under Column B below to prepare the corresponding products listed under C below.

COLUMN A 4,4-dimethylbenzophenone oxime, 2,2'-dimethylbenzophenone oxime, 2,2'-dichlorobenzophenone oxime, 4-nitrobenzophenone oxime, 4,4'-dichlorobenzophenone oxime, 3-dimethylaminobenzophenone oxime, 4,4'-dimethoxybenzophenone oxime, 4,4'-di(ethylthio)-benzophenone oxime, 2-t-butylbenzophenone oxime, 3,3-dibromobenzophenone oxime, 4-ethoxybenzophenone oxime, 2,2-di(butylthio)-benzophenone oxime, 4,4-dinitrobenzophenone oxime, 4,4-bis(diethylamino)-benzophenone oxime, a,a-dinaphthylketone oxime, B,B-dinaphthylketone oxime, 5-oximinodibenzo[a,d]cycloheptene, 5-oximino-l0,l l-dihydrodibenzo[a,dlcycloheptene, 9-oximinofluorene, IO-Oximinoxanthene, lO-oximinothioxanthene,

l. A compound selected from the group consisting of a compound of the formula Ole (U and its corresponding nitrone; wherein,

R is hydrogen, methyl, or ethyl;

R is alkyl of one to six carbon atoms, halomethyl, phenyl, or mono substituted phenyl wherein the substituent is halo, nitro, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halomethyl;

l \\:Z l e l I 5 (;:N--0"Cn-s m 0-n-s-Rz R and R taken together is ethylene, propylene, or

tetramethylene; and Z is a carbon-carbon single bond or a carbon-carbon double bond. l5

2. A compound of claim 1 wherein Z is a carboncarbon single bond.

3. A compound of claim 2 wherein R is hydrogen and R is methyl.

4. A compound of claim 2 wherein R is hydrogen and R is ethyl.

5. A compound of claim 2 wherein R is hydrogen and R is isopropyl.

6. A compound of claim 2 wherein R is hydrogen and R is n-propyl. 

2. A compound of claim 1 wherein Z is a carbon-carbon single bond.
 3. A compound of claim 2 wherein R1 is hydrogen and R2 is methyl.
 4. A compound of claim 2 wherein R1 is hydrogen and R2 is ethyl.
 5. A compound of claim 2 wherein R1 is hydrogen and R2 is isopropyl.
 6. A compound of claim 2 wherein R1 is hydrogen and R2 is n-propyl. 